Theoretical characterization of sulfur-to-selenium substitution in an emissive RNA alphabet: impact on H-bonding potential and photophysical properties

Abstract

We employ density functional theory (DFT) and time-dependent DFT (TDDFT) calculations to investigate the structural, energetic and optical properties of a new computationally designed RNA alphabet, where the nucleobases, A,G, C, andU (ts-bases), have been derived by replacing sulfur with selenium in the previously reported tz-bases, based on the isothiazolo[4,3-d]pyrimidine heterocycle core. We find out that the modeled non-natural bases have minimal impact on the geometry and energetics of the classical Watson-Crick base pairs, thus potentially mimicking the natural bases in a RNA duplex in terms of H-bonding. In contrast, our calculations indicate that H-bonded base pairs involving the Hoogsteen edge of purines are destabilized as compared to their natural counterparts. We also focus on the photophysical properties of the non-natural bases and correlate their absorption/emission peaks to the strong impact of the modification on the energy of the lowest unoccupied molecular orbital. It is indeed stabilized by roughly 1.1-1.6 eV as compared to the natural analogues, resulting in a reduction of the gap between the highest occupied and the lowest unoccupied molecular orbital from 5.3-5.5 eV in the natural bases to 3.9-4.2 eV in the modified ones, with a consequent bathochromic shift in the absorption and emission spectra. Overall, our analysis clearly indicates that the newly modelled ts-bases are expected to exhibit better fluorescent properties as compared to the previously reported tz-bases, while retaining similar H-bonding properties. In addition, we show that a new RNA alphabet based on size-extended benzo-homologated ts-bases can also form stable Watson-Crick base pairs with the natural complementary nucleobases.

Supramolecular insight into the substitution of sulfur by selenium, based on crystal structures, quantum-chemical calculations and biosystem recognition

“…Theoretical characterization of the impact of sulfur-toselenium substitution on hydrogen-bonding potential and photophysical properties in an emissive RNA alphabet has shown that the replacement of sulfur with selenium in derived nucleobases has a minimal effect on the geometries and energies of base pairs in the classical Watson-Crick model, while base pairs in the Hoogsteen model are destabilized, compared with natural pairs (Chawla et al, 2018).…”

Computational design and characterization of new thieno‐expanded tricyclic purine analogs

“…For instance, the structural, energetic, bonding aspects, and optical properties of the th‐bases were theoretically investigated by Samanta et al and Gedik et al Similarly, the electronic structure and optical properties of the tz‐bases were theoretically investigated by Valverde et al, Chawla et al and the current group . In addition, the sulfur‐to‐selenium substitution effects on H‐bonding potential and photophysical properties of the tz‐bases were also theoretically examined by Chawla et al…”

“…Recent progresses include a tricyclic cytidine analogue with turn‐on response to duplex formation, a novel quadracyclic adenosine FRET pair, a versatile and exceptionally bright fluorescent pentacyclic adenine analog, an emissive interbase FRET pair, and the emissive isomorphic RNA alphabets (th‐bases and tz‐bases) . Notably, the isomorphic th‐bases and tz‐bases synthesized by Tor's group have gained much attention . For instance, the structural, energetic, bonding aspects, and optical properties of the th‐bases were theoretically investigated by Samanta et al and Gedik et al Similarly, the electronic structure and optical properties of the tz‐bases were theoretically investigated by Valverde et al, Chawla et al and the current group .…”

“…electronic structure and optical properties of the tz-bases were theoretically investigated by Valverde et al, [29] Chawla et al [30] and the current group. [31] In addition, the sulfur-to-selenium substitution effects on H-bonding potential and photophysical properties of the tz-bases were also theoretically examined by Chawla et al [32] Size-expansion is a very important and well-established strategy for designing FBAs, [33] and many of such FBAs have been developed. [34][35][36][37][38][39][40][41][42][43] Prototypical examples are the benzo-expanded x-bases [35] and y-bases, [36] and the naphtho-expanded yy-bases [37] synthesized by Kool's group.…”

“…[35b] Recent progresses of such expanded nucleobases include tricyclic thiophene purine analogs, [38] naphtho-expanded xx-bases, [39,40] size-expanded Janus AT nucleobases, [41] hetero-ring-expanded purine analogs, [42,43] the benzo-homologated xth-RNA, [33a] xtz-RNA [33b] and its sulfur-to-selenium substituted xts-RNA. [32] One focus of our research has involved the study of photophysical properties of nucleobase analogs. In the present work, we computationally design four new thieno-expanded purine analogs by using the size-expansion strategy.…”